What are neural tube defects?

Formation of the Neural Tube

The neural tube
develops out of the neural plate and differentiates into the brain and spinal
cord. Neurulation is a complex process of organized gene expression in which thickened epithelial
cells that make up the neural plate change shape, migrate, and differentiate at
precise intervals to form a hollow tube. During convergent extension (CE), cells
narrow and lengthen and the borders fold, forming the neural groove, which becomes
progressively deeper with cell division. The neural tube begins
to form as the dorsal folds meet and fuse along the midline. Closure begins in the
cervical region, extends along the rostral/caudal plane, and ends at the anterior
and posterior neuropores around the twenty-fourth and twenty-eighth days after
conception, respectively. At the cephalic (head) end of the neural tube, three
cavities form and differentiate into the forebrain, midbrain, and hindbrain;
midway, the walls (epithelium) develop into cells of the
nervous system; the caudal (tail) end becomes the spinal cord. NTDs can result
when any of the steps in this process is disrupted.

Classification of Neural Tube Defects

Anencephaly is caused by disruption of the anterior neuropore, resulting in a
lack of significant areas of the brain and skull. The region normally occupied by
the cerebral hemispheres consists of a formless mass of highly vascular connective
tissue; most of the bones of the skull are simply missing. Almost all infants are
stillborn or die soon after birth. Encephalocele is a related condition in which
parts of the brain and the sac-like membrane covering it protrude outside the
skull; severity of dysfunction depends on the extent of neural tissue
involvement.

The severe form of spina bifida is characterized by herniation of neural
tissues and cystic swelling. Protrusion of both the meninges
(protective coatings) and the spinal cord through the open site is called a
myelomeningocele or meningomyelocele and results in dysfunction to nerves at and
below the site. The higher up the lesion is along the vertebral column, the
greater the nerve damage is. Most born with a myelomeningocele also have
hydrocephalus (80–85 percent) and a neurogenic bladder (up to 90 percent); many
require surgery for a tethered cord (20–50 percent) and/or Arnold-Chiari
malformation (33 percent).

Meningocele is a more moderate form in which the sac-like protrusion contains
meninges and spinal fluid but no spinal cord and usually causes no nerve damage.
Occult spinal dysraphism is a mild form in which there may be a dimple with tufts
of hair on the lower back.

Prevalence of Neural Tube Defects

Rates of NTDs have been declining (as much as 30 to 40 percent) in most areas
of the world, due to dietary changes made when spina bifida was linked to a lack
of absorption of folic acid. Nevertheless, spina bifida occurs in 1 to 2 of every
2,500 births worldwide.

Women deficient in vitamin B12 have up to five times the risk of
having an affected child. Besides folate deficiency, other risk factors include
certain genetic factors, such as a previous NTD birth (2 percent higher risk),
obesity, Hispanic ethnicity, and exposure to high temperatures. At-risk women are
advised to have their alpha-fetoprotein levels measured. Amniocentesis
and ultrasound can help in detecting an NTD in the developing fetus.

Genetic Aspects of Neural Tube Defects

Normal folate metabolism is necessary for DNA synthesis and methylation, cell
division, and tissue growth. Folate pathway genes have been extensively examined
for their association with NTDs. A mutation in the methylenetetrahydrofolate
reductase gene (MTHFR) was the first genetic link to NTD risk,
and it causes decreased enzyme activity in folate absorption. The
A222V allele of MTHFR and single nucleotide
polymorphisms (SNPs) of betaine-homocysteine S-methyltransferase
(BHMT) are both gene mutations that are suspected of posing
significant risk for NTDs.

Many genes have been studied in animal models and implicated in NTDs. The
signal
transduction protein of the sonic hedgehog gene
(SHH) controls the loci of bending points during conversion of
the neural plate to the neural fold. The Ras association domain family member 7
(RASSF7), a gene with protein product, is required to complete
mitosis in the neural tube. The most important of the
altered gene expressions include abnormalities in wingless (Wnt)
signaling and mutations in Vang-like 1 (VANGL1), a gene that is
part of the Wnt signaling pathway and controls the activity of
genes needed at specific times during development. Wnt signaling
is involved in many aspects of embryonic development, including formation of the
neural tube, in which it directs cell polarity orientation, regulation of nerve
cell migration, and CE movements. The methylenetetrahydrofolate dehydrogenase
(MTHFD1) gene, involved in the folate pathway, has also been
studied extensively for its possible role in the pathogenesis of NTDs.

Despite these strides, the genetic basis of NTDs remains complex and poorly understood, involving a combination of multiple gene-gene and gene-environment interactions. To form, the neural tube requires precise spatial and temporal gene expression. Specific genes determine cell fate and lateral inhibition pathways, others control the frequency of mitosis, gene receptors are involved in fusion in the cranial epithelium or fusion of the neural fold, and regulatory genes program development of the brain stem and midbrain.

Impact

Research linking the C677T mutation in the
MTHFR gene to NTDs was an important milestone that resulted in
a significant reduction in the incidence of these birth defects after the US Food
and Drug Administration (FDA) issued a mandate in 1998 that manufacturers fortify
all enriched cereal grain products with folic acid. This was preceded by an
advisory from the US Public Health Service in 1992 that all women of childbearing
age take a daily supplement of folic acid. In 2009, the US Preventive Services
Task Force (USPSTF) updated the advisory, increasing the 0.4 milligram (mg)
recommended dosage of folic acid to a range of 0.4 to 0.8 mg.

Because neurulation occurs so early in fetal development, it cannot be examined
in humans. However, researchers have been able to detect some faulty
neurulation-related genes in humans. Three missense mutations of the
protein-coding VANGL1 gene (V239I,
R274Q, and M328T) were identified in patients
with spina bifida. The V239I variant was found to nullify
interactions of VANGL1 Disheveled (Dvl) proteins 1, 2, 3. (A related study found
VANGL1 mutant mice produced offspring with NTDs.) Researchers
conducted a whole genome association analysis of forty-five families who had a
previous anencephalic pregnancy and identified eleven SNPs on six different genes
as possible risk factors for anencephaly. Two of these, the InaD-like
(Drosophila) gene (INADL) and the myelin
transcription factor
gene (MYT1L), were found to be involved in neural tube closure.
INADL is located on chromosome 1 and affects the movement of
cells to their correct position; MYT1L is located on chromosome 2
and controls other genes that affect the development of the nervous system.

Although research has indicated that faulty genes involved in folate metabolism
and/or neurulation pathways are the most likely candidate genes for NTDs, there
are still many questions as to the genetic mechanisms of neural tube closure.
Because many genes tend to multitask and participate in more than one function, it
is difficult to analyze single gene expressions. The key to lowering the incidence
of NTDs is continued research to elucidate other gene variants and signaling
pathways that affect neurulation and folate metabolism.

Key Terms



alpha-fetoprotein

:

plasma protein produced by the fetus; elevated level indicates risk of an NTD




anencephaly

:

NTD caused by failure of the cerebral hemispheres of the brain and cranium to develop; incompatible with life





Arnold-Chiari malformation


:

herniation of the hindbrain in which the cerebellar vermis and part of
the brain stem become pushed into the cervical spine




neural tube

:

the embryonic precursor to the spinal cord and brain that forms as the neural plate folds and normally closes by the twenty-eighth day of gestation





spina bifida


:

NTD meaning “open spine” that is caused by failure of the posterior
neuropore to close normally during gestation, resulting in protrusion of
a portion of the spinal cord outside the vertebral column; surgically
closed shortly after birth





hydrocephalus


:

excessive accumulation of cerebrospinal fluid in the brain, causing
enlargement of the ventricles; requires surgical insertion of a shunt to
drain




neurogenic bladder

:

malfunctioning bladder caused by paralytic pelvic floor, resulting in incontinence, urinary reflux, and UTIs; requires lifelong clean intermittent catherization (CIC) and kidney function assessment




tethered cord

:

low-lying position of the spinal cord when it scars to the skin after surgical closure and becomes stretched as the child grows





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